Use of 6-allyl-2-amino-5,6,7,8-tetrahydro-4H-thiazol[5,4-d]azepine for releasing growth hormone

ABSTRACT

The use of 6-allyl-2-amino-5,6,7,8-tetrahydro-4H-thiazolo[4,5-d]azepine and the pharmacological acid addition salts thereof for the release of growth hormone.

The invention relates to the use of a thiazoloazepine derivative and thepharmacologically acceptable acid addition salts thereof for the releaseof growth hormone, e.g. for treating growth disorders.

German Offenlegungsschrift No. 20 40 510 describes thiazolo-andoxazolo-derivatives of general formula ##STR1## wherein R₁ represents ahydrogen atom, an alkyl group with 1 to 4 carbon atoms optionallysubstituted by a hydroxyl group, a benzoyl group optionally substitutedby a halogen atom or by a methyl or methozy group, or an allyl group andX represents an oxygen or sulphur atom, and the physiologicallyacceptable acid addition salts thereof with inorganic or organic acids.

It is also known from this offenlegungsschrift that the compounds ofgeneral formula I have valuable pharmacological properties; thespecification describes both antitussive and hypotensive properties,depending on X. A delayed-release form for the oral treatment ofhypertension and angina pectoris is disclosed in DE-OS No. 28 36 387.U.S. Pat. No. 4,400,378 also describes an anti-glaucoma property ofcompounds of general formula I.

Moreover, 6-allyl-2-amino-5,6,7,8-tetrahydro4H-thiazolo[4,5-d]azepine isdescribed innumerous scientific publications under the name B-HT 920.Applications relating to a second medical indication were filed in theform of DE-OS No. 35 02 365, relating to a composition for lowering theprolactin serum level, and in DE-OS No. 35 03 963, concerning acomposition for the treatment of Parkinsonism. Compounds which bringabout the release of growth factor are already known from numerouspublications and patent applications (Bibl.: F. X. Coude et al., Trendsin Biotechnology 1984, Volume 2, page 83 ff; M. O. Thorner in "TheLancet", July 16, 1983, page 119 ff; EP-OS No. 0 136 475). These arepolypeptides, generally with a sequece of 40 amino acids. In theEnglish-language publications, these peptides are also referred to as"Growth Hormone Releasing Factor" (GRF). These compounds may be preparedby conventional chemical synthesis or also by genetic engineering. Owingto the complex structure of these peptides it has hitherto not beenpossible to produce them in large quantities by conventional synthesisand even genetic engineering does not produce them any more cheaply on alarger scale.

Surprisingly, it has been found that B-HT 920 causes the release ofgrowth hormone in humans. BH-T 920 and the physiologically acceptableacid addition salts thereof are suitable for preparing a drug for thetreatment of growth disorders. It may be used to treat diseases whichare based on a reduced secretion of growth hormone, e.g. growthdisorders in children such as restricted growth, and also in reducedmetabolism, e.g. malnutrition, cachexia caused by tumours orchemotherapy; chronic anoxaemia caused by respiratory insufficiency orcardiopathy, kidney failure. Other indications include bone fractures,burns, wound healing and the acceleration of blood production.

For diagnostic purposes, B-HT 920 can be used to stimulate the releaseof growth hormone and thus determine whether there is sufficient growthhormone in the hypophysis.

For the release of growth hormone, B-HT 920 and the acceptable acidaddition salts thereof (e.g. B-HT 920 Cl₂) may be incorporated in theconventional galenic preparations for oral, rectal, parenteral ortransdermal use.

The single dose by oral route for humans is normally between 0.05 mg and0.3 mg, preferably 0.1 to 0.25 mg. When administered several timesthroughout the day the total dosage may be between 0.6 and 1.0 mg.

The following are clinical trials investigating the release of growthhormone by B-HT 920 Cl₂.

The tests are carried out with six male subjects ranging in age from 21to 46. Each subject was given 0.15 to 0.2 mg of B-HT 920 Cl₂ in tabletform.

The measurement of the growth hormone in the serum was carried out usinga standard radioimmunological process.

The serum levels are determined before and after administration. Theblood samples were taken through a fixed vein cannula which was put intoposition 1 hour before administration of the substance and determinationof the 0 level. The measurements obtained are listed in Table I. Theyare given in ng/ml.

    ______________________________________                                        Dosage    Test    0 level  Hours after medication                             B-HT920Cl.sub.2                                                                         subject t = 0    1    2     3   5    8                              ______________________________________                                        0.15 mg   1       0.3      0.5  0.3   3.5 4.4  0.4                            0.15 mg   2       0.4      0.3  0.3   0.5 3.3  0.3                            0.20 mg   3       1.5      0.4  2.5   9.5 1.0  0.5                            0.15 mg   4       0.3      0.32 1.7   0.3 0.2  0.2                            0.15 mg   5       0.3      7.3  0.6   0.4 0.2  0.3                            0.15 mg   6       0.4      20.0 12.4  1.4 0.4  0.4                            ______________________________________                                    

The substance is very well tolerated and no undesirable effects such asdryness of the mouth, fatigue or dizziness are experienced.

The following Examples describe the preparation of some pharmaceuticalforms:

EXAMPLE I

Coated tablet core

    ______________________________________                                        Composition:                                                                  1 tablet core contains                                                                            100    microg                                             B-HT 920 Cl.sub.2                                                             Lactose             38.45  mg                                                 Corn starch         10.0   mg                                                 Gelatine            1.0    mg                                                 Magnesium stearate  0.5    mg                                                 ______________________________________                                    

Method

The mixture of the active substance with lactose and corn starch isgranulated with a 10% aqueous gelatine solution by passing through a 1mmscreen, dried at 40° C. and passed through the same screen again. Thegranules thus obtained are mixed with magnesium stearate and compressedto form tablet cores. This procedure should be carried out in a darkenedroom.

    ______________________________________                                        Weight of core:      50 mg                                                    Punch:               5 mm, convex                                             ______________________________________                                    

The tablet cores thus obtained are coated in known manner with a coatingconsisting essentially of sugar and talc. The finished coated tabletsare polished with beeswax.

    ______________________________________                                        Weight of coated tablet:                                                                              100 mg                                                ______________________________________                                    

EXAMPLE II

Suppositories

    ______________________________________                                        1 suppository contains                                                        ______________________________________                                        B-HT 920 Cl.sub.2      100.0 microg                                           Suppository mass (e.g. Witepsol W 45)                                                                1690.0 mg                                              ______________________________________                                    

Method

The finely powdered substance is stirred, by means of an immersionhomogenizer, into the molten suppository mass which has been cooled to40° C. At 35° C. the mass is poured into slightly chilled moulds.

EXAMPLE III

Ampoules containing 200 mcg of B-HT 920

    ______________________________________                                        1 ampoule contains:                                                           ______________________________________                                        B-HT 920            200 microg                                                Citric acid         7.0 mg                                                    Sec. sodium phosphate 2H.sub.2 O                                                                  3.0 mg                                                    Sodium phyrosulphite                                                                              1.0 mg                                                    Distilled water ad  1.0 ml                                                    ______________________________________                                    

Method

The buffer substances, active substance and sodium pyrosulphite aredissolved successively in the distilled water which has been cooledunder a current of CO₂. The solution is made up to the specified volumewith distilled water and filtered to remove any pyrogens.

Packaging: in brown ampoules under protective gas

Sterilization: 20 minutes at 120° C.

The ampoule solution must be prepared and packaged in a darkened room.

EXAMPLE IV

Coated tablets containing 1 mg of B-HT 920 Cl₂

    ______________________________________                                        1 tablet core contains:                                                       ______________________________________                                        B-HT 920 Cl.sub.2                                                                              100 microg                                                   Lactose          36.0 mg                                                      Corn starch      12.4 mg                                                      Gelatine         1.0 mg                                                       Magnesium stearate                                                                             0.5 mg                                                       ______________________________________                                    

Method

    ______________________________________                                        Analogously to Example I                                                      ______________________________________                                        Weight of core     50      mg                                                 Punch:             5       mm, convex                                         Weight of coated tablet:                                                                         100     mg                                                 ______________________________________                                    

EXAMPLE V

Gelatine capsules containing 250 mcg of B-HT 920 Cl₂

    ______________________________________                                        1 capsule contains:                                                           ______________________________________                                        B-HT 920 Cl.sub.2                                                                              250 microg                                                   Corn starch      85.7 mg                                                      ______________________________________                                    

Method

The substances are intensively mixed and packed into opaque capsules ofsuitable size.

Example of preparation of a transdermal form

Composition:

    ______________________________________                                        9.744  g of Eudragit ® E 30 D (Messrs. Rohm, Darmstadt)                   0.600  g of Eudrgit ® E 100 (Messrs. Rohm, Darmstadt)                     1.656  g of B-HT 920 C12                                                      12.000 g solids                                                               6.000  g acetone                                                              22.000 g methanol                                                             100.000                                                                              g solution                                                             ______________________________________                                    

The Eudragit® E 100 is previously dissolved in acetone, then theEudragit® E 30 D and half the methanol are added and the mixture isstirred. When a homogeneous solution has been formed, the activesubstance and the remaining methanol are added in batches. The resultingsolution is poured onto a film drawing apparatus (made by Erichsen) ontoa prepared backing layer impervious to the active substance and spreadwith a doctor blade at a position of 0.6 mm. After 10 minutes' drying asecond and then a third layer are applied with the doctor blade in thesame position. After drying, a film is obtained in a thickness of 100microns. The film is then packaged and, for use, is attached to the skinby means of a suitable sticking plaster.

What is claimed is:
 1. A method of inducing the release of growthhormone in a warm-blooded animal in need thereof which comprisesadministering to said animal a growth hormone releasing amount of6-allyl-2-amino-5,6,7,8-tetrahydro-4H-thiazolo-[5,4-d]azepine or thepharmacologically acceptable acid addition salts thereof.